SUMMARY Substantial improvement in survival in men with prostate cancer (PCa) has focused attention on the high prevalence of sexual dysfunction, physical dysfunction, and low energy, which are important contributors to suboptimal health-related quality of life (HRQOL) in prostate cancer survivors. The pathophysiology of these symptoms in prostate cancer survivors is multifactorial, but androgen deficiency is a frequent, remediable contributor. In healthy hypogonadal men, testosterone replacement therapy (TRT) improves these symptoms, suggesting that it also might do so for survivors of PCa who have testosterone deficiency. However, because testosterone promotes the growth of metastatic prostate cancer, there has been concern about administering TRT to prostate cancer survivors. Open label trials and retrospective analyses have reported very low recurrence rates in men who have undergone radical prostatectomy and received TRT, but neither safety nor efficacy have been evaluated in a randomized trial in this population. The South West Oncology Group patient advocates have deemed this a high priority question for prostate cancer survivors. Our primary aim is to conduct a double-blind, placebo-controlled, parallel-group, randomized trial to determine whether testosterone replacement is safe and efficacious in improving sexual function in men with androgen deficiency, who have undergone radical prostatectomy for pT2,N0,M0, Gleason score ?6 disease and are at very low risk of disease recurrence. A secondary aim is to determine whether TRT improves muscle mass and strength, and self reported and performance-based measures of physical function. The third objective is to determine the effects of TRT on wellbeing and affect, mood, energy, and quality of life. The trial will enroll men, 40 years or older, who have undergone radical prostatectomy for organ-localized prostate cancer (pT2,N0,M0); with Gleason score ?6; pre-treatment PSA <10 ng/mL; and undetectable PSA (<0.1 ng/mL) for at least two years after radical prostatectomy; who have symptoms of sexual dysfunction, fatigue, or physical dysfunction; and who have unequivocally low total (average of two morning levels <275 ng/dL) or free testosterone (<60 pg/mL) levels. Participants will be randomized to receive placebo or testosterone gel for 12 weeks. Changes in sexual activity, sexual desire, erectile function, sexual distress, sexual life quality, lean body mass, muscle strength, physical function, affectivity balance, and energy will be evaluated at baseline, 6 and 12 weeks. We will monitor hematocrit, PSA, and biochemical recurrence, defined as? PSA of ?0.2 ng/mL with a confirmatory level of ?0.2 ng/mL?. Careful selection of subjects with very low risk of recurrence, rigorous safety monitoring, pre-specified stopping rules, and oversight by an independent DSMB will minimize risks. Extensive preliminary data support the feasibility of this trial. Randomized trial design, a multidisciplinary team, careful attention to statistical power, and selection of symptomatic men with unequivocally low testosterone will insure the validity of the assessment of efficacy and safety of testosterone therapy in this needy patient population.